The biggest challenge associated with the JAVELIN Renal 101 trial, said senior author Toni K. Choueiri, MD, is deciding when to use this combination.

The JAVELIN Renal 101 study enrolled 886 patients with advanced or metastatic RCC who were randomized 1:1 to receive either 10 mg/kg of avelumab intravenously every 2 weeks plus 5 mg of oral axitinib twice daily in 6-week cycles or 50 mg of oral sunitinib once daily for a 4-weeks-on/2-weeks-off schedule.

The primary endpoint was PFS in PD-L1–positive patients. In this patient population, the median PFS was 13.8 months (95% CI, 11.1-NE) with the combination versus 7.2 months (95% CI, 5.7-9.7) with sunitinib, which translated to a 39% reduction in the risk of disease progression or death (HR, 0.61; 95% CI, 0.475-0.790; P <.0001). The ORRs were 55.2% with axitinib/avelumab and 25.5% with sunitinib, according to results presented at the 2018 ESMO Congress.

In the overall population, the median PFS with the combination of avelumab and axitinib versus sunitinib was 13.8 months and 8.4 months, respectively (HR, 0.69; 95% CI, 0.563-0.840; P = .0001). The ORRs were 51.4% with avelumab/axitinib and 25.7% with sunitinib. Adverse events (AEs) associated with the combination were manageable.

OncLive: Please discuss the JAVELIN Renal 101 study.

Choueiri: This was presented at the plenary session at the 2018 ESMO Congress and was the only kidney cancer abstract presented in that session. It was a pivotal phase III trial testing the combination of axitinib, a VEGF tyrosine kinase inhibitor (TKI), plus the PD-L1 inhibitor avelumab versus sunitinib. It included patients with RCC of all risk groups. These patients were previously untreated with systemic therapy. This is was an important trial building on other trials.

The initial phase I trial showed that the combination is tolerable at full dose of each agent. Axitinib was given at 5 mg twice a day, and the response rates were over 50%. We moved directly to a phase III trial. In addition, when we looked at PD-L1 patients and the overall population, both endpoints were met. An important endpoint where we do not yet have results is overall survival; this is a very important endpoint for frontline treatment.

Interestingly, when you look at the different risk groups, patients seem to benefit irrespective of them. Toxicity was actually manageable, but of course immune-related AEs is something you have to watch out for. Only 4% of patients had to stop treatment with the combination due to toxicity.

Where do these results fit into the treatment paradigm?

The story is evolving, and it has to continue doing so because the first-line landscape of metastatic RCC is extremely complicated. There are approved TKIs and immunotherapies, and we have to figure out which ones to use in which patients. Based on data we saw right before the 2018 ESMO Congress, it appears that the combination of axitinib and pembrolizumab (Keytruda) is on its way to approval.

There are several other pivotal phase III trials ongoing. There is one with lenvatinib (Lenvima), an important VEGFR inhibitor, in combination with pembrolizumab. This study is well-advanced in terms of accrual. Cabozantinib (Cabometyx) is also being combined with checkpoint inhibitors. If all these studies are positive, we are going to have an extremely crowded space in RCC.

What is an area of kidney cancer that requires more research?

We can talk about biomarkers, but nothing is ready for clinical practice. We can talk about PD-L1 expression knowing that some of these patients still benefit from nivolumab (Opdivo) and ipilimumab (Yervoy). When you combine VEGF with immune checkpoint inhibitors, it's completely different. With the crowded space we will have in the frontline setting, the attention in the next 5 years is going to have to be on novel targets.

We are also going to have to see how we can sequence later lines of therapy. What can we learn from these 5-plus regimens besides what we see clinically? This is going to be crucial moving forward. For example, if a patient has an autoimmune disease, I would not start with checkpoint blockade. If a patient needed very significant and quick reduction of the tumor because they are symptomatic, then you would have to look at the regimen, no matter what, with the highest response rate. We continue to build on the standard. Ten years ago, no one would have thought that sunitinib, which was standard of care, would essentially be moved out. Things are getting better.